Symptoms and clinical relevance: A dilemma for clinical trials on prevention of venous thromboembolism

Henri Bounameaux; Giancarlo Agnelli

doi:10.1160/TH12-08-0627

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 109(04): 585-588
DOI: 10.1160/TH12-08-0627

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Schattauer GmbH

Symptoms and clinical relevance: A dilemma for clinical trials on prevention of venous thromboembolism

Henri Bounameaux

¹Division of Angiology and Haemostasis and Faculty of Medicine, University Hospitals of Geneva, Geneva, Switzerland

,

Giancarlo Agnelli

²Internal and Cardiovascular Medicine – Stroke Unit, University of Perugia, Perugia, Italy

› Author Affiliations

Abstract

Summary

The outcomes of thromboprophylactic trials have been debated for decades. Recently, the 9^th edition of the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines based their strong recommendations only on patient-important outcomes. Practically, symptoms were considered the crucial element. Consequently, studies that primarily aimed at reducing venographic thrombi were considered less pertinent than studies that focused on symptomatic thrombosis. In the present viewpoint, we challenge the argument that “symptomatic” and “clinically relevant” are interchangeable. In particular, the case is made that asymptomatic events may be clinically relevant and that asymptomatic venographically detected thrombosis is a clinically relevant surrogate outcome for fatal pulmonary embolism.

Keywords

Prophylaxis - pulmonary embolism - thrombosis - surgery

Full Text

References

References
1 Silverstein MD, Heit JA, Mohr DN. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585-593.
2 Cohen AT, Agnelli G, Anderson FA. et al. VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98: 756-764.
3 US Department of Health and human services. The Surgeons General’s call to action to prevent deep vein thrombosis and pulmonary embolism. 2008
4 Geerts WH, Bergqvist D, Pineo GF. et al. Prevention of venous thromboembolism. Chest 2008; 133 Suppl 381S-453S.
5 Mavrakanas T, Bounameaux H. The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism. Pharmacol Ther 2011; 130: 46-58.
6 Wells PS, Lensing AWA, Davidson BL. et al. Accuracy of ultrasound for diagnosis of deep venous thrombosis in asymptomatic patients after orthopedic surgery. A meta-analysis. Ann Intern Med 1995; 122: 47-53.
7 Schellong SM, Beyer J, Kakkar AK. et al. Ultrasound screening for asymptomatic deep vein thrombosis after major orthopaedic surgery: the VENUS study. J Thromb Haemost 2007; 05: 1431-1437.
8 Segers AEM, Prins MH, Lensing AWA. et al. Is contrast venography a valid surrogate outcome measure in venous thromboembolism prevention studies?. J Thromb Haemost 2005; 03: 1099-1102.
9 Fleming TR, DeMets DL. Surrogate end points in clinical trials : are we being misled?. Ann Intern Med 1996; 125: 605-613.
10 Guyatt GH, Eikelboom JW, Gould MK. et al. Approach to outcome measurement in the prevention of thrombosis in surgical and medical patients: Anti-thrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. American College of Chest Physicians. Chest 2012; 141: 185S-194S.
11 Huber O, Bounameaux H, Borst F. et al. Postoperative pulmonary embolism after hospital discharge: an underestimated risk. Arch Surg 1992; 127: 310-313.
12 Planes A, Vochelle N, Darmon JY. et al. Risk of deep-vein thrombosis after hospital discharge in patients having undergone total hip replacement : double-blind randomised comparison of enoxaparin versus placebo. Lancet 1996; 348: 224-228.
13 Bergqvist D, Benoni G, Bjorgell O. et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against thromboembolism after total hip replacement. N Engl J Med 1996; 335: 696-700.
14 Dahl OE, Andreassen G, Aspelin T. et al. Prolonged thromboprophylaxis following hip replacement surgery - results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin (Fragmin(). Thromb Haemost 1997; 77: 26-31.
15 Lassen MR, Borris LC, Anderson BS. et al. Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasty - The Danish Proplonged Prophylaxis (DaPP) Study. Thromb Res 1998; 89: 281-287.
16 Hull RD, Pineo GF, Francis C. et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs. In-hospital warfarin/out-of hospital placebo in hip arthroplasty patients : a double-blind, randomized comparison. North-American Fragmin Trial Investigators. Arch Intern Med 2000; 160: 2208-2215.
17 Cohen AT, Bailey CS, Alikhan R. et al. Extended thromboprophylaxis with low molecular weight heparin reduces symptomatic venous thromboembolism following lower limb arthroplasty. Thromb Haemost 2001; 85: 940-941.
18 Bounameaux H. Integrating pharmacologic and mechanical prophylaxis. Thromb Haemost 1999; 82: 931-937.
19 Robinson KS, Anderson DR, Gross M. et al. Ultrasonographic screening before hospital discharge for deep venous thrombosis after arthroplasty : the post-arth-roplasty screening study. A randomized controlled trial. Ann Intern Med 1997; 127: 439-445.
20 Leclerc JR, Gent M, Hirsh J. et al. The incidence of symptomatic venous thromboembolism during and after prophylaxis with enoxaparin : a multi-institutional cohort study of patients who underwent hip or knee arthroplasty. Arch Intern Med 1998; 158: 873-878.
21 Heit JA, Elliott CG, Trowbridge AA. et al. Ardeparin sodium for extended out-of hospital prophylaxis against venous thromboembolism after total hip or knee replacement. Ann Intern Med 2000; 132: 853-861.
22 Eriksson BI, Borris LC, Friedman RJ. et al. RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
23 Kakkar AK, Brenner B, Dahl OE. et al. RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hoip arthroplasty: a double-blind, randomized controlled study. Lancet 2008; 372: 31-39.
24 Lassen MR, Ageno W, Borris LC. et al. RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776-2786.
25 Turpie AG, Lassen MR, Davidson BL. et al. RECORD4 Investigators. Rivaroxaban versus enoxaparin after total knee arthroplasty (RECORD4): a randomized trial. Lancet 2009; 373: 1673-1680.
26 Ricotta S, Iorio A, Parise P. et al. Post discharge clinically overt venous thromboembolism in orthopaedic surgery patients with negative venography - An overview analysis. Thromb Haemost 1996; 76: 887-892.
27 Beyer-Westendorf J, Halbritter K, Platzbecker H. et al. Central adjudication of venous ultrasound in VTE screening trials : reasons for failure. J Thromb Haemost 2011; 09: 457-463.